Product of diuretic activity and process



United States Patent PRODUCT OF DIURETEC ACTIVITY AND PRQCESS T0 PREPARESAME Zoltan Fiildi, Dorottya Heidt, nee Lanyi, and Rezso Kiinig, all ofBudapest, Hungary, assignors to Chinoin Gyogyszer-es VegyeszetiTerrnekek Gyara R11, Budapest, Hungary, a firm No Drawing. Filed June28, 1960, Ser. No. 39,405 Claims priority, application Hungary Oct. 1,1959 3 Claims. (Cl. 260-443) We have found that a new compound theelementary analysis of which corresponds to formula C H N ClS O andwhich is a derivative both of 5-chloro-2,4-disulphamyl-aniline and of6-chloro-7-sulphamyl-benZo-dihydro-l,2,4-thiadiazine-1,l-dioxide as wellis a very elfective diuretic. This compound melts at about 227230 C.with decomposition (yellowish foam) and exhibits an intense redcolouration with resorcinol wetted by concentrated sulphuric acid. Sincethis compound can be prepared by the action of hexarnethylene-tetramineeither on 5-chloro-2,4-disulphamyl-aniline (C H N ClS O or on6-chloro-7-sulphamyl-benZo-dihydro-1,2,4-thiadiazine- 1,1-dioxide (C I-lN ClS O the excess of atoms (C H N related to the latter formula,probably has the following structure:

which corresponds to half a molecule of hexamethylenetetramine. Theformula C H N ClS O is in agreement, among others, with the structuralformula which depicts anN,N-diazocyclopentarnethylene-N,N-methylene-derivative, the bondingsites of the diazocyclopentamethylene and of the methylene groups beingunsettled. Thus, the precise structure of the compound is yet notcleared; this is, however, relating to the pharmacological activity ofthis compound of no relevance.

The new compound may be used as medicament in the form of pharmaceuticalpreparations, for example, as tablets, dragees or capsules, suspensions,emulsions; these preparations may also contain, in combination, othertherapeutically useful substances, such as hypotensive agents.

The new compound of empirical formula can be obtained by the action ofhexamethylenetetramine on 2,4-disulphamyl-5-chloroaniline or on6-chloro-7- sulphamyl-benzo-dihydro-1,2,4-thiadiazine-dioxide.Preferably, 2,4-disulphamyl-5-chloro-aniline is subjected to the actionof hexamethylenetetrarnine. This action can take place by heating thereactants in a medium containing water, preferably consisting of water.One can use organic solvents, as well, preferably in the presence ofwater.

When 6-chloro-7-sulphamyl-benzo-dihydro-1,2,4-thiadiaZine-l,l-dioxide issubjected to the action of hexamethylenetetramine, the same media, asmentioned above, further concentrated ammonia, preferably at roomtemperature, can be used.

Further details are to be found in the examples.

Examples (1) 28.5 g. (0.1 mole) of 2,4-disulphamyl-5-chloroaniline, 14g. (0.1 mole) of hexamethylenetetramine and 125 ml. of water arerefluxed for 3 hours, while stirring. The reaction mixture remains asuspension. Ammonia is evolved. Next day, the bright crystals arebrought on a suction filter, washed with water (2 x 25 ml.), then driedover phosphoric anhydride at room temperature to 3,123,603 Patented Mar.3, 1964 ice yield 35 g. of the product (MP. at about 227 C., witheffervescence) The elementary analysis of the compound (C:32.60%;H=3.55%; N=18.72%) suggests formula From the five N-atoms two can beeasily found by the following titration: 181 mg. of the product aretitrated with 20 ml. of 0.1 n-HCI for half an hour on the steambath. Theresulting solution is cooled, 2.5 ml. of ethanol added and titrated with0.1 n-NaOH (indicator methyl red). 10 ml. of 0.1 n-NaOl-I are consumed,corresponding to 7.74% N (calculated for 2 N-atoms: 7.65% N).

Some milligrams of the product when placed on a mixture of resorcinoland cone. sulphuric acid exhibit an intense red colour reaction. Theproduct is slightly soluble in dilute hydrochloric acid, readily solublein 2 molecules of cold 0.1 n-NaOH, hardly soluble in organic solvents.One 5;. of the product dissolved in boiling water (33 ml.) deposits oncooling crystals (0.74 g.) of 6-chloro-7- sulphamyl-benzo-dihydro- 1,2,4-thiadiazine- 1 1 -dioxide.

The product exhibits pronounced diuretic (natriuretic) andantihypertensive activities. The enhanced excretion of urine and theenhanced amount of chloride-ion in the excreted urine can be easilyobserved on white rats even in peroral doses of 0.2 mg. per kg.body-weight.

(2) In following the procedure as given in Example 1, but using 0.2 mole(i.e. 28 g.) of hexamethylenetetramine instead of 0.1 mole, one obtains34.8 g. of the product with melting point 227 C. (effervescence). Theother properties of the product are, likewise, identical with that ofExample 1.

This example reveals that an excess of hexamethylenetctrarnine (over 1molecule) does not take part in the reaction.

(3) One proceeds as given in Example 1, but using only 0.05 mole (i.e. 7g.) of hexamethylenetetramine instead of 0.1 mole. The product weighs29.2 g. and melts at 226227 C. (eifervescence). The somewhat low N-content (17.9%) indicates, however, a small contamination with thestarting disulphamyl-3-chloro-aniline.

(4) 29.7 g. (0.1 mole) of6-chloro-7-sulphamyl-benzodihydro-l,2,4-thiadiaZine-1,l-dioxide, 14 g.(0.1 mole) of hexamethylenetetramine and water ml.) are refluxed forthree hours while stirring. The reaction mixture remains a suspensionand evolution of ammonia can be observed. After cooling and allowing tostand for some hours, the crystals are isolated, washed with water anddried. One obtains 35.75 g. (97% of the theoretical) of the product aswhite crystals, showing a melting point of 228 C. (effervescence). Its Ncontent (Kjeldahl) is 18.6%. It is identical with the product ofExample 1. With resorcinol and conc. sulphuric acid it exhibits anintense red colour reaction.

(5) 285 mg. of 2,4-disulphamyl-S-chloro-aniline are dissolved in 1.5 ml.of 54%di-methoxy-diethylether and a solution of 140 mg. ofhexamethylenetetramine in 0.1 ml. of water added. The mixture is kept inan oil-bath of C. for 3 hours. Bright crystals result. After cooling andallowing to stand for 1 /2 hours, the crystals are brought onto asuction filter, washed with two portions of 6,13-dimethoxy-diethylether(0.2 ml. each), then washed with 0.5 ml. of ether. 355.5 mg. of theproduct are obtained; M.P. 227 C. with decompensation (yellowish foam).The product is identical with that of Exampie 1. It exhibits withresorcinol and cone. sulphuric acid a strong cinnober red colouration.

(6) The same starting materials are used as given in the precedingexample, but 2 ml. of ethanol and 0.5 ml. of water are used as diluents.The mixture is heated on the steam-bath for 3 hours. In the first halfan hour a solution occurs, followed by precipitation of white crystals.Next day, these are collected, washed with three portions of ethanol(0.5 ml. each), then dried. 295 mg. of the product result, melting at228 C. (yellowish foam). The product is identical with that ofExample 1. It exhibits red colour reaction with resorcinol wetted withcone. sulphuric acid.

(7) 594 mg. of 6-chloro-7-sulphamyl-benzodihydro-1,2,4-thiadiazine1,1-dioxide are dissolved in cone. ammonia (2 ml.), and140 ml. of hexamethylenetetrarnine added. Soon, crystallisation sets inand the reactionmixture turns to a white crystal pulp. It is allowed tostand for two hours, preventing escape of ammonia, and more someadditional hours in an open vessel in order to reduce the concentrationof ammonia. Then, the crystals are filtered on a suction filter, washedwith 1 ml. of Water and dried over phosphoric acid. Snow white crystals(725 mg.) result, which melt at 230 C. (yellowish foam).

All melting points are uncorrected.

We claim:

1. A process for the preparation of a compound of diuretic activity, theelementary analysis of which corresponds to formula C H N ClS O andwhich is a derivative of 5-chloro-2,4-disu1phamyl-aniline, the compoundmelting at about 227-230 C. with decomposition and exhibiting an intensered colouration with resorcinol wetted by concentrated sulphuric acid,which comprises heating at reflux temperature one molecule of 5-chloro-2,4-disulphamyl-aniline with an amount of 0.5-2 molecules ofhexamethylenetetramine in water as reaction medium.

2. A compound of diuretic activity corresponding to the formula C H NClS O melting at about 227230 C. with decomposition into a yellowishfoam, exhibiting an intense red coloration with resorcinol wetted withconcentrated sulphuric acid, obtained by refluxing one molecule of5-chloro-2,4-disulphamyl-aniline with an amount of 0.5-2 molecules ofhexamethylenetetrarnine in Water as diluent.

3. A process to prepare a new compound of diuretic activity,corresponding to the formula C H N ClS O melting at about 227230 C. withdecomposition into a yellowish foam, exhibiting an intense redcoloration with resorcinol wetted with concentrated sulfuric acid, whichconsists in refluxing for three hours one molecule of 5-chloro-2,4-disulphamyl-aniline with an amount of 0.5-2 molecules ofhexamethylenetetrarnine in water as diluent.

References Cited in the file of this patent Organic Chemistry, pages215-217 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N003 l23 603 March 3 1964 Zoltan FZildi et ale It is hereby certified thaterror appears in the above numbered pat ent requiring correction andthat the said Letters Patent should read as corrected below" Column 2line 8 for "titrated read triturated column 2 lines 19 to 21 strike outOne go of the product dissolved in boiling water (33 mlo) deposits oncooling crystals (074 g.,) of 6-chloro7-su1phamyl-benz0-dihydro-l 2 ithiadiazine-l 1-dioxide'.,

Signed and sealed this 17th day of November 1964 r (SEAL) Anest:

ERNEST We SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

2. A COMPOUND OF DIURETIC ACTIVITY CORRESPONDING TO THE FORMULAC10H14N5CIS2O4 MELTING AT ABOUT 227-230* C. WITH DECOMPOSITION INOT AYELLOWISH FOAM, EXHIBITING AN INTENSE RED COLORATION WITH RESORCINOLWETTED WITH CONCENTRATED SULPHURIC ACID, OBTAINED BY REFLUXING ONEMOLECULE OF 5-CHLORO-2,4-DISULPHAMYL-ANILINE WITH AN AMOUNT OF 0.5-2MOLECULES OF HEXAMETHYLENETRAMINE IN WATER AS DILUENT.